Peripheral and central galactose/β-galactoside-related alterations in ischemic stroke: Clinical associations of circulating LPH and experimental evidence for Glb1 and galectin-3

Abstract Aims Circulating metabolic biomarkers for acute ischemic stroke (AIS) remain incompletely characterized. We examined galactose-related alterations at both peripheral and central levels, focusing on serum lactase-phlorizin hydrolase (LPH) as a candidate circulating biomarker and on the roles of Glb1 and galectin-3 (Gal-3) in ischemic neuronal injury. Methods Untargeted serum metabolomics was first performed in an exploratory AIS cohort to identify altered carbohydrate-related metabolic patterns. Serum LPH was then assessed in an independent hospital-based cohort and a community-based cross-sectional cohort of 1,810 participants. Transient middle cerebral artery occlusion/reperfusion (tMCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary neurons were used to examine the effects of Glb1 knockdown and Gal-3 inhibition with GB1107, alone and in combination, on neuronal injury and oxidative stress. Results Serum LPH was significantly higher in patients with AIS and discriminated AIS from healthy controls with an AUC of 0.908. In the community cohort, higher LPH remained associated with stroke status after adjustment for major vascular risk factors. Metabolomic analysis also showed alterations in galactose-related metabolism. Glb1 and Gal-3 expression increased in ischemic rat brain tissue and OGD/R-exposed neurons. Targeting either Glb1 or Gal-3 reduced neuronal injury and oxidative stress. Combined intervention produced greater protection than either treatment alone. Conclusion Circulating LPH is associated with ischemic stroke and may have value as a peripheral metabolic biomarker. Glb1 and Gal-3 contribute to ischemic neuronal injury and may represent neuroprotective targets. Together, these findings reveal complementary peripheral metabolic alterations and central injury responses involving Glb1 and Gal-3 in ischemic stroke.